Glaucoma is a group of ocular disorders, characterized by degeneration of the optic nerve. It is one of the leading causes of blindness worldwide. One major risk factor for developing glaucoma is family history: several different inherited forms of glaucoma have been described.
Primary congenital or infantile glaucoma (gene symbol:GLC3) is an inherited disorder that accounts for 0.01-0.04% of total blindness. It is characterized by an improper development of the aqueous outflow system of the eye, which leads to elevated intraocular pressure, enlargement of the globe or cornea (i.e., buphthalmos), damage to the optic nerve, and eventual visual impairment. Pathogenesis of GLC3 remains elusive despite efforts to identify a single anatomic defect. At least two chromosomal locations associated with the disease have been identified: one locus at 2p21 (GLC3A) (Sarfarazi, M. et al., Genomics 30:171-177 (1995); and a second locus at 1p36 (GLC3B) (Akarsu, A. N. et al., Hum. Mol. Gen. 5(8):1199-1203 (1996)). Other specific loci, including a region of 6p and chromosome 11, have been excluded (Akarsu, A. N. etal., Am. J. Med. Genet. 61:290-292 (1996)).
Primary open angle glaucoma (gene symbol: GLC1) is a common disorder characterized by atrophy of the optic nerve resulting in visual field loss and eventual blindness. GLC1 has been divided into two major groups, based on age of onset and differences in clinical presentation.
Juvenile-onset primary open angle glaucoma (GLC1A) usually manifests in late childhood or early adulthood. The progression of GLC1A is rapid and severe with high intraocular pressure, is poorly responsive to medical treatment, and is such that it usually requires ocular surgery. GLC1A was initially mapped to the q21-q31 region of chromosome 1 (Sheffield, V. C. et al., Hum. Mol. Genet. 4:1837-1844 (1995)); mutations in the gene for trabecular meshwork inducible glucocorticoid response (TIGR) protein, located a chromosome 1q24, have been identified as associated with GLC1A glaucoma (Stone, E. M. et al., Science 275:668-670 (1997); Stoilova, D. et al., Opthamalic Genetics 18(3):109-118 (1997); Adam, M. F. et al., Hum. Mol. Genet. 6:2091-2097 (1997); Michels-Rautenstrauss, K. G., et al., Hum. Genet. 102:103-106 (1998); Mansergh, F. C. et al., Hum. Mutat. 11:244-251 (1998)).
Adult- or late-onset primary open angle glaucoma (GLC1B) followed by direct mutation analysis by restriction enzyme digestion is the most common type of glaucoma. It is milder and develops more gradually than juvenile-onset primary open angle glaucoma, with variable onset usually after the age of 40. GLC1B is associated with slight to moderate elevation of intraocular pressure, and often responds satisfactorily to regularly monitored medical treatment. However, because the disease progresses gradually and painlessly, it may not be detected until a late stage when irreversible damage to the optic nerve has already occurred. Linkage, haplotype and clinical data have assigned a locus for GLC1B to the 2cen-q13 region as well as a new locus 3q21-q22 (Stoilova, D. et al., Genomics 36:142-150 (1996)). Further evidence has identified several additional loci for primary open angle glaucoma. GLC1C, an adult-onset POAG gene, has been mapped to 3q (Wirtz, M. K. et al., Am. J Hum. Genet. 60:296-304 (1997)); GLC1D has been mapped to 8q23 (Trifan, O. C. et al., Am. J. Ophthalmol. 126:17-28 (1998)); GLC1E has been mapped to 10p15-p14 (Sarfarazi, M. et al., Am. J. Hum. Genet. 62: 641-652 (1998)).
Because of the insidious nature of glaucoma, a need remains for a better and earlier means to diagnose or predict the likelihood of development of glaucoma, so that preventative or palliative measures can be taken before significant damage to the optical nerve occurs.